Compounds for the treatment of kinase-dependent disorders
Inventors
Bannen, Lynne Canne • Bui, Minna • Jiang, Faming • Tso, Kin • Wang, Yong • Xu, Wei
Assignees
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Publication Number
US-12503438-B2
Publication Date
2025-12-23
Expiration Date
Abstract
Disclosed herein are compounds of Formula (I) which inhibit, regulate and/or modulate tyrosine kinase receptors, particularly Axl and Mer signal transduction pathways related to the changes in cellular activities, compositions containing the compounds, methods of using the compounds to treat kinase-dependent diseases and conditions, and methods for making the compounds.
Core Innovation
The invention relates to cyclopropane-1,1-dicarboxamide compounds defined by Formula (Ia) and pharmaceutically acceptable salts thereof. The compounds are defined by a structural framework specifying ring A and fused ring systems, and substituent patterns through variables including R1, R2, R3, R4, Rb, Rc, R8, R9, Y, and ring nitrogen oxidation. The framework uses integer subscripts that constrain the structural scope, including n, m, q, and additional structural subscripts in Formula II embodiments.
Ring A is selected from phenyl and multiple heteroaryl or heterocycloalkyl rings, and the quinoline ring nitrogen atom on Formula (Ia) is optionally oxidized. R8 and R9 are either independent substituents or together form a fused 5-10 membered heteroaryl or fused 5-10 membered heterocycloalkyl, optionally substituted with Rg substituents and containing 0-2 additional heteroatoms selected from N and S as ring members. Additional substituent options are provided for Rb and other positions, including C1-6 alkyl, C1-6 alkoxy, CN, halo, OH, oxo, NH2, HO-C1-6 alkyl, haloalkyl, haloalkoxy, cycloalkyl-related groups, and alkyl- and heterocycle-containing sulfonyl and carbonyl-related substituent classes.
The disclosure also includes Formula II embodiments with additional constraints on u and m and optional substitution of ring B with 1 or 2 groups independently selected from halo, oxo, and (C1-C6) alkyl. The patent further discloses specific cyclopropane-1,1-dicarboxamide derivatives, including compounds with a quinolinyl-oxyphenyl scaffold, 4-fluorophenyl substituents, substituted pyrazole and other heteroaryl variants, and named heteroaryl motifs such as pyridinyl, triazolyl, imidazolyl, dihydrofuran, and oxolane. The compounds are also presented as pharmaceutically acceptable salts, and some examples are described with analytical data and stereochemical variants.
Claims Coverage
The provided claims coverage centers on broad Formula (Ia) compound claims and related Formula IIa/IIb embodiments, together with enumerated cyclopropane-1,1-dicarboxamide derivatives. The independent claim set combines a broadly defined quinoline-containing scaffold with extensive ring and substituent constraints, and separate claim content recites specific named derivative compounds. Overall, the coverage includes multiple inventive features across the Formula (Ia) family and the specific enumerated compounds.
Compound of Formula (Ia) with defined ring A and substituent framework
A compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the listed phenyl or heteroaryl/heterocycle set; R1 is H, C1-6 alkyl, C1-6 alkoxy, halo, or C1-6 alkyl-NHC(O); each R3 is independently selected from the listed substituent set; R4 is C1-6 alkyl or halo; R8 is H or C1-6 alkyl; R9 is H or R8 and R9 together with the atoms form a fused 5-10 membered heteroaryl or fused 5-10 membered heterocycloalkyl with optional Rg substitution and 0-2 additional heteroatoms selected from N and S; each Rb is independently selected from the listed substituent set; and the ring nitrogen atom on the quinoline is optionally oxidized, with n, m, and q constrained by the stated integer ranges.
Formula (Ib)/(Ic) compound with constrained subscript m
A compound of Formula (Ib) or Formula (Ic) (or a pharmaceutically acceptable salt thereof) defined with constraints including the fused ring configuration described for ring B and wherein the subscript m is an integer of 1, 2, or 3.
R3 restricted to hydrogen or halo
The compound of Formula (Ia) (or a pharmaceutically acceptable salt thereof) in which R3 is either H or halo.
Formula IIa/IIb compound with constrained u and m and optional ring B substitution
A compound (or a pharmaceutically acceptable salt thereof) that is a compound of Formula IIa or Formula IIb in which the substituent subscripts u and m satisfy u=0 or 1 and m=1 or 2, and wherein ring B may be optionally substituted with 1 or 2 groups independently selected from halo, oxo, and (C1-C6) alkyl.
Selected cyclopropane-1,1-dicarboxamide derivatives
A compound selected from a listed set of specific 1-N-(4-fluorophenyl)-1-N-[4-[7-...quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide variants (including multiple enumerated pyrazolyl/heteroaryl substituent variants) or a pharmaceutically acceptable salt thereof.
The claimed subject matter centers on cyclopropane-1,1-dicarboxamide compounds defined by Formula (Ia) with a defined ring A set, a substituent framework for R1, R3, R4, R8, R9, and Rb, optional oxidation of the quinoline ring nitrogen, and integer constraints for n, m, and q. Dependent and related claims narrow the structure through Formula (Ib)/(Ic), Formula IIa/IIb constraints, restriction of R3 to hydrogen or halo, optional ring B substitution, and separate claims to specific enumerated cyclopropane-1,1-dicarboxamide derivatives.
Stated Advantages
Provides therapeutic benefit for treating hyperproliferative disorders.
Includes objective and subjective improvements, including partial responses and clinical endpoint measures.
Uses response categories based on irRC, including irCR and irPR.
Supports measurable disease and progression markers, including tumor burden, progression-free survival, overall survival, and overall response rate.
Describes an initial worsening followed by stabilization.
Inhibits or modulates Axl and Mer receptor tyrosine kinase signaling pathways associated with cancer and other kinase-dependent diseases.
Provides compounds, pharmaceutical compositions, and methods for treating kinase-dependent diseases by administering therapeutically effective amounts of the compounds.
Documented Applications
Treatment of hyperproliferative disorders including neoplasia, tumor, cancer, and metastasis.
Combination therapy using an immunotherapeutic agent together with a compound of the invention.
Use of immunotherapeutic modalities including checkpoint inhibitors and CAR-T and other engineered immune cells.
Use of checkpoint inhibitor concepts and vaccine/radioconjugate frameworks.
TAM kinase imaging/assays using labeled compounds and assays for TAM kinase ligands.
Treatment of kinase-dependent diseases, including cancer, via inhibiting protein kinase and modulating Axl and Mer receptor tyrosine kinase signaling pathways.
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